颈动脉窦电刺激对肥胖性心脏重构的保护作用及其机制研究

The global prevalence of obesity is escalating. Human obesity is characterized by sympathetic nervous activation and vagal nervous suppression. Autonomic dysfunction plays an important role in metabolic abnormalities and cardiac remodeling. .Carotid baroreflex stimulation (CBS) has been applied to treat hypertension and heart failure via inhibition of sympathetic nervous activity. Our previous study showed that 6 hours of CBS could withdraw sympathetic activity; high-fat diet induced obese mice developed cardiac remodeling; 8 weeks of CBS could prevent rats from high-fat diet induced weight gain, visceral fat accumulation, glycometabolic abnormalities and insulin resistance. These data indicates that CBS may have cardiac protective effects on obesity. .We hypothesize that CBS may suppress cardiac remodeling through ameliorating autonomic neural remodeling and metabolic disorder in obesity..To test this hypothesis, we plan to establish obese rat models by high-fat diet feeding, observe the impacts of low level CBS on metabolisms and autonomic nervous remodeling without blood pressure or heart rate reduction, and then illustrate the effects on cardiac remodeling including cardiac hypertrophy, apoptosis, fibrosis, endoplasmic reticulum stress and substrates metabolic abnormalities. The effects of CBS on cellular signaling pathway would also be investigated. The results will provide new insights into the role of autonomic neural remodeling in the underlying mechanisms of obesity associated cardiac remodeling and provide new strategies to prevent cardiac remodeling in patients with obesity.

全球肥胖发生率居高不下，肥胖常合并交感神经张力增高和迷走神经张力下降，植物神经功能异常是加重代谢异常和导致心脏重构的重要原因。.颈动脉窦电刺激（CBS）抑制交感神经张力，近年来用于高血压和心衰的临床治疗。我们前期研究发现：6小时的CBS即可抑制交感神经张力；高脂饮食诱导的肥胖小鼠出现明显的心脏重构；8周的CBS可以抑制高脂饮食诱导的大鼠肥胖、内脏脂肪沉积、糖耐量异常和胰岛素抵抗，并显示出一定的心脏保护作用。.我们假设:CBS通过干预植物神经重构，调控机体和心肌代谢异常来抑制肥胖性心脏重构。.本项目拟用高脂饮食诱导大鼠肥胖模型，观察低强度CBS在不影响血压和心率前提下，对肥胖大鼠植物神经重构和机体代谢的影响，从心肌肥厚、凋亡、纤维化、内质网应激、底物代谢异常等角度观察其对心脏重构的影响，从细胞内信号通路的角度研究其机制。有望从植物神经重构的角度为探索肥胖性心脏重构的机制和治疗方法提供新思路。

交感神经系统（SNS）过度激活是肥胖的重要特征，是引起心脏重塑的原因之一。颈动脉窦压力感受器刺激（CBS）已经被证明是一种可以抑制交感神经活性、改善心脏重构的新方法。.在本研究中，采用16周高脂饮食诱导肥胖大鼠模型。观察高脂饮食大鼠脂质代谢及氧化应激状况，并观察CBS对高脂饮食大鼠心脏重构的影响及其相关的机制研究。结果显示16周的高脂肪饮食可成功建立肥胖大鼠模型，主要表现为体重、血压增加，心率变异性降低，脂代谢紊乱，氧化应激和心脏重构等。CBS 对肥胖大鼠的体重增加、胰岛素抵抗、糖脂代谢紊乱、心率变异性 (HRV) 受损、脂质积累过多、氧化应激和心脏重塑具有保护作用。另外，转录组测序分析显示，单胺氧化酶A（MAO-A）在高脂饮食大鼠的心肌组织中明显上调，而CBS治疗使其下调。同时， CBS也使PI3K/AKT/mTOR信号通路下调。在体外研究中，去甲肾上腺素 (NE) 在新生大鼠心肌细胞 (NRCMs) 中诱导了类似的肥胖性心脏重塑改变，包括氧化应激、脂质积累和炎症反应。 MAO-A 抑制明显逆转了 NE 的以上损害，并且降低了AKT 的磷酸化水平。.上述结果表明，CBS显著抑制了肥胖大鼠交感神经过度激活，并改善了心脏重塑，其机制可能与MAO-A和PI3K-AKT-mTOR信号通路的下调有关。